There is an inverse relationship between ambient calcium levels and PTH release that is curvilinear rather than proportional. This relationship between PTH and extracellular calcium contrasts with the influence of the calcium ion as a secretagogue in most other secretory systems in which elevations in this ion enhance release of the secretory product. This distinction between the parathyroid cell and other secretory cells is maintained intracellularly, where elevations rather than decreases in cytosolic calcium correlate with de creased PTH release. Alterations in extracellular fluid calcium levels are transmitted through a parathyroid plasma membrane calcium- sensing receptor (CaSR) that couples through a Gq/ 11- protein complex to phospholipase C. Increases in extracellular calcium lead to increases in inositol 1,4,5- trisphosphate (IP3) and mobilization of intracellular calcium stores. The CaSR also couples to a Gi- protein complex thereby inhibiting cyclic AMP production.
The human CaSR comprises 1078 amino acids with a large extracellular domain (ECD) (~600 amino acids), a seven- transmembrane- spanning domain and a cytoplasmic tail. The CaSR is a member of group C of the G- protein- coupled receptor (GPCR) superfamily that includes the metabotropic glutamate, γ- aminobutyric acid- B, and taste and odorant receptors. These receptors function as dimers with the ECDs of each monomer having a so- called Venus flytrap domain consisting of two lobes that close upon the ligand leading to conformational changes in the trans membrane domain of the receptor allowing coupling of G proteins to the intracellular loops and the cytoplasmic tail. The CaSR has a low affinity for Ca2+ appropriate for it monitoring the relatively high levels of the mineral ion in the blood. Besides the parathyroid, the CaSR is also expressed in other cells having Ca2+- sensing functions, such as those of the kidney tubule, the calcitonin secreting thyroid C- cells and in diverse other organs and tissues such as brain, bone, and cartilage, haematopoietic stem cells, keratinocytes, gastrointestinal tract, mammary gland, placenta, and vascular smooth muscle. Neomycin binds the receptor, which may account for the toxic renal effects of aminoglycoside antibiotics.
Inherited abnormalities of the CASR gene located on chromo some 3q13.3- 21 can lead to either hypercalcaemia or hypocalcaemia depending upon whether they are inactivating or activating, respectively. Heterozygous loss- of- function mutations give rise to familial (benign) hypocalciuric hypercalcaemia type 1 (FHH1) in which the lifelong hypercalcaemia is asymptomatic. The homozygous condition manifests itself as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcaemia and the bony changes of hyperparathyroidism. Cases of neonatal hyperparathyroidism (NHPT) may be caused by a paternal or de novo mutation in the CASR gene. FHH is heterogeneous and FHH2 and FHH3 are due to heterozygous inactivating mutations in the GNA11 gene (encoding the Gα11 protein) and AP2S1 gene (encoding a subunit of the adaptor protein com plex important for cell internalization of the CaSR), respectively. The disorder autosomal dominant hypocalcaemia type 1 (ADH1) is due to gain- of- function mutations in the CASR gene. ADH1 may be asymptomatic or present with neonatal or childhood seizures. Because of the overactive CaSR in the nephron, these patients are at a greater risk of developing renal complications during vitamin D therapy than patients with idiopathic hypoparathyroidism. ADH2 is due to heterozygous activating mutations in the GNA11 gene. A common polymorphism in the intracellular tail of the CaSR, Ala to Ser at position 986, has a modest effect on the serum calcium concentrations in healthy individuals. CASR polymorphisms might also affect urinary calcium excretion and therefore the CASR is a candidate gene for involvement in disorders such as idiopathic hypercalciuria, and primary hyperparathyroidism.
The CaSR is a target for phenylalkylamine compounds— so- called calcimimetics— which are allosteric stimulators of the CaSR’s affinity for cations. These orally active compounds have been ap proved for use in patients with chronic kidney disease and tertiary hyperparathyroidism, in parathyroid cancer, and in primary hyperparathyroidism when patients are not surgical candidates for parathyroidectomy. By their direct action on the parathyroid gland CaSR they provide an effective medical means of lowering PTH secretion and reducing hypercalcaemia. Ongoing clinical trials in patients with mild primary hyperparathyroidism (PHPT) have shown that calcimimetics reduce serum calcium and PTH levels and increase serum phosphate levels but do not significantly affect bone turnover or bone mineral density (BMD).
The CaSR expressed in the developing parathyroid glands— and in the placenta— plays an important role in regulating fetal calcium concentrations. Normally, the fetal blood calcium level is elevated above the maternal level. This depends upon the action of PTHrP re leased from the placenta on placental calcium transport. Disruption of the CaSR, as shown by studies in CaSR- deficient mice, causes fetal hyperparathyroidism and hypercalcaemia due to fetal bone re sorption. The transfer of calcium across the placenta is reduced and renal calcium excretion is increased.
Some patients with inactivating anti- CaSR autoantibodies, often associated with autoimmune disorders such as sprue or auto immune thyroid disease, present as an FHH phenocopy termed acquired hypocalciuric hypercalcaemia (AHH). The anti- CaSR antibodies are directed against the ECD and interfere with elevated extracellular Ca2+- mediated suppression of PTH release and per turb Ca2+- sensing in the kidney, thereby closely mimicking FHH. Activating autoantibodies that inhibit PTH secretion have been identified in some patients with autoimmune hypoparathyroidism and the CaSR has also been identified as a self- antigen in patients with autoimmune polyendocrine syndrome type 1 (APS1) or acquired hypoparathyroidism associated with autoimmune hypothyroidism or idiopathic hypoparathyroidism. The activating auto antibodies are directed against epitopes in the ECD of the receptor.
In vivo, PTH mRNA levels are markedly stimulated by de creased circulating calcium concentrations. This occurs, in part, by a posttranscriptional mechanism whereby hypocalcaemia stabilizes and hypercalcaemia destabilizes the PTH mRNA. Prolonged hypocalcaemia in vivo may stimulate DNA replication, cell division, and the production of increased numbers of parathyroid cells or para thyroid hyperplasia. This would increase the synthesis of proteins, including PTH, within the hypercellular parathyroid gland and ultimately would increase PTH release. In primary parathyroid gland hyperfunction resulting in hyperparathyroidism, alterations in the calcium- sensing mechanism may manifest as a set- point error, producing a shift to the right of the curve relating PTH secretion to extracellular calcium levels. Consequently, elevated concentrations of extracellular fluid calcium may be required to reduce PTH secretion, resulting in an adenomatous or hyperplastic parathyroid gland that is incompletely suppressed by calcium. Such a mechanism may underlie the observation that an increase in the mass of parathyroid tissue like that produced by transplantation can be associated with hypercalcaemia. The parathyroid glands of patients with primary and severe uremic secondary hyperparathyroidism have reduced CaSR expression as assessed by immunostaining. Loss of a functional CaSR as in humans with NSHPT or in mice in which the Casr gene has been ablated leads to severe parathyroid hyperplasia. If basal secretion per cell produces a significant amount of bio active PTH, the cumulative increase in this basal or non- calcium- suppressible secretion arising from an increase in parathyroid cells could also be responsible for the hypercalcaemia. The precise mechanistic relationship of extracellular calcium to parathyroid cell growth remains to be determined.
